A Randomised Double Blind (Sponsor Unblinded), Single and Repeat Ascending Dose First Time in Human Study in Healthy Subjects, Cold Urticaria and Chronic Spontaneous Urticaria Subjects to Investigate Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of GSK2646264
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- GlaxoSmithKline
- Enrollment
- 34
- Locations
- 1
- Primary Endpoint
- Number of Participants With AEs and SAEs Part B
Study Overview
Brief Summary
This First Time in Human (FTIH) study, which will be performed in three parts, is designed to investigate the safety, local tolerability, pharmacokinetics and pharmacodynamics after single and repeat topical applications of up to 2 strengths of GSK2646264 and corresponding placebo within the same subject, in healthy adult subjects (Part A), subjects with cold urticaria (CU, Part B) and subjects with chronic spontaneous urticaria (CsU, Part C). The study will also measure short term effects of GSK2646264 on the number and size of weals in subjects with CsU, and in healthy subjects and subjects with CU following provocation tests.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Part A: Dose group 1
Subjects will be treated topically with 0.5 % GSK2646264 cream and placebo cream on an area of approximately 12 x 3 centimetre (cm) on the volar aspect of the arm which approximates to 0.2% total body surface area (BSA), on each arm. On Day 2 and Day 3 subjects will receive active treatment and placebo on the same arms as on Day 1, with the percentage BSA being 1% on Day 2 and 5% on Day 3.
Intervention: GSK2646264 0.5% topical cream (Drug)
Part A: Dose group 1
Subjects will be treated topically with 0.5 % GSK2646264 cream and placebo cream on an area of approximately 12 x 3 centimetre (cm) on the volar aspect of the arm which approximates to 0.2% total body surface area (BSA), on each arm. On Day 2 and Day 3 subjects will receive active treatment and placebo on the same arms as on Day 1, with the percentage BSA being 1% on Day 2 and 5% on Day 3.
Intervention: Placebo (Drug)
Part A: Dose group 2
Subjects will be treated topically with 1 % GSK2646264 cream and placebo cream on the morning and evening of Day 1 starting at the final % BSA dosed at Day 3 in group 1 which is anticipated to be 5%. In dose group 2, the starting BSA will increase to 10% at Day 3 and then 20% by Day 5. Administration of the evening (PM) dose will be dependent on the data from Part A Dose group 1.
Intervention: GSK2646264 0.5% topical cream (Drug)
Part A: Dose group 2
Subjects will be treated topically with 1 % GSK2646264 cream and placebo cream on the morning and evening of Day 1 starting at the final % BSA dosed at Day 3 in group 1 which is anticipated to be 5%. In dose group 2, the starting BSA will increase to 10% at Day 3 and then 20% by Day 5. Administration of the evening (PM) dose will be dependent on the data from Part A Dose group 1.
Intervention: GSK2646264 1% topical cream (Drug)
Part A: Dose group 2
Subjects will be treated topically with 1 % GSK2646264 cream and placebo cream on the morning and evening of Day 1 starting at the final % BSA dosed at Day 3 in group 1 which is anticipated to be 5%. In dose group 2, the starting BSA will increase to 10% at Day 3 and then 20% by Day 5. Administration of the evening (PM) dose will be dependent on the data from Part A Dose group 1.
Intervention: Placebo (Drug)
Part B
Cold urticaria subjects will receive treatment to 4 defined areas (right and left arms and legs). Subjects will be treated with maximum tolerated strength of GSK2646264 cream (0.5% or 1%) and placebo cream in morning or in morning and evening to 2 specified areas of ~5% BSA on the subject's legs for the CU assessment and to 2 specified areas of 0.2% BSA on the volar aspect of the arm. The maximum tolerated strength and evening dosing will be dependent on the data from the Part A
Intervention: GSK2646264 0.5% topical cream (Drug)
Part B
Cold urticaria subjects will receive treatment to 4 defined areas (right and left arms and legs). Subjects will be treated with maximum tolerated strength of GSK2646264 cream (0.5% or 1%) and placebo cream in morning or in morning and evening to 2 specified areas of ~5% BSA on the subject's legs for the CU assessment and to 2 specified areas of 0.2% BSA on the volar aspect of the arm. The maximum tolerated strength and evening dosing will be dependent on the data from the Part A
Intervention: GSK2646264 1% topical cream (Drug)
Part B
Cold urticaria subjects will receive treatment to 4 defined areas (right and left arms and legs). Subjects will be treated with maximum tolerated strength of GSK2646264 cream (0.5% or 1%) and placebo cream in morning or in morning and evening to 2 specified areas of ~5% BSA on the subject's legs for the CU assessment and to 2 specified areas of 0.2% BSA on the volar aspect of the arm. The maximum tolerated strength and evening dosing will be dependent on the data from the Part A
Intervention: Placebo (Drug)
Part C
Chronic spontaneous urticaria subjects will be treated with the maximum tolerated strength of GSK2646264 cream from Part A (0.5% or 1%) and placebo cream onto defined areas (right and left arms and, legs and front torso) from Days 1 to 7. The total % BSA for an individual subject will be decided by the investigator prior to randomization. The maximum % BSA and the frequency of dosing will be decided after part A of the study.
Intervention: GSK2646264 0.5% topical cream (Drug)
Part C
Chronic spontaneous urticaria subjects will be treated with the maximum tolerated strength of GSK2646264 cream from Part A (0.5% or 1%) and placebo cream onto defined areas (right and left arms and, legs and front torso) from Days 1 to 7. The total % BSA for an individual subject will be decided by the investigator prior to randomization. The maximum % BSA and the frequency of dosing will be decided after part A of the study.
Intervention: GSK2646264 1% topical cream (Drug)
Part C
Chronic spontaneous urticaria subjects will be treated with the maximum tolerated strength of GSK2646264 cream from Part A (0.5% or 1%) and placebo cream onto defined areas (right and left arms and, legs and front torso) from Days 1 to 7. The total % BSA for an individual subject will be decided by the investigator prior to randomization. The maximum % BSA and the frequency of dosing will be decided after part A of the study.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Number of Participants With AEs and SAEs Part B
Time Frame: Up to Day 19
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. Data is presented according to the percentage BSA as it impacted safety
Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part B
Time Frame: Day 3 and follow up (Day 17 to Day 19)
Clinical chemistry parameters assessed were ALT, albumin (low \<30 grams/liter), alkaline phosphatase, AST, calcium (low \<2 millimoles/liter and high \>2.75 millimoles/liter), chloride (low \<98 millimoles/liter and high \>106 millimoles/liter), creatinine (high \>159 micromoles/liter), direct bilirubin, GGT (low \<8 units/liter and high \>78 units/liter), glucose (low \<3 millimoles/liter and high \>11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low \<3 millimoles/liter and high \>5.5 millimoles/liter), sodium (low \<130 millimoles/liter and high \>150 millimoles/liter), total bilirubin, total protein and urea/BUN (low \<2.9 and high \>7.1). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.
Number of Participants With AEs and SAEs Part A
Time Frame: Up to Day 11
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Number of Participants With AEs and SAEs Defined by Severity Part A
Time Frame: Up to Day 11
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. AE and SAE were categorized as mild=an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities, moderate=an event that was sufficiently discomforting to interfere with normal everyday activities and severe=an event that prevented normal everyday activities.
Change From Baseline in Vital Sign Parameter Heart Rate for Part C
Time Frame: Baseline and (Day 1 pre-dose), Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15, follow-up (Day 23)
Vital sign heart rate was measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed.
Number of Participants With AEs and SAEs Defined by Severity Part C
Time Frame: Up to 23 days
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. AE and SAE were categorized as mild=an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities, moderate=an event that was sufficiently discomforting to interfere with normal everyday activities and severe=an event that prevented normal everyday activities.
Change From Baseline in Vital Sign Parameter Heart Rate for Part B
Time Frame: Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up (Day 17 to Day 19)
Vital sign heart rate was measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.
Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part A
Time Frame: Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 4 and follow-up (Day 5 to Day 7)
Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2, Day 3, Day 4 and follow-up. Baseline was defined as assessments performed at Day 1 (pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.
Change From Baseline in Vital Sign Parameters SBP and DBP for Part A
Time Frame: Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up (Day 9 to Day 11)
Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up. Baseline was defined as assessments performed at Day 1 (pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.
Change From Baseline in ECG Parameters for Part B
Time Frame: Baseline (Day -1) and Day 3 (pre-dose) and follow-up (Day 17 to Day 19)
Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, QTcB, QTcF intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.
Change From Baseline in ECG Parameters for Part C
Time Frame: Baseline (Day -1) and Day 7 (pre-dose) and follow-up (Day 23)
Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, QTcB, QTcF intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed.
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Part A
Time Frame: Up to Day 7
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. Safety population comprised of all participants who took at least one dose of study treatment.
Number of Participants With AEs and SAEs Part C
Time Frame: Up to Day 23
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Change From Baseline in Vital Sign Parameter Heart Rate for Part A
Time Frame: Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up (Day 9 to Day 11)
Vital sign heart rate was measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.
Change From Baseline in Electrocardiogram (ECG) Parameters for Part A
Time Frame: Baseline (Day -1) and Day 8 and follow-up (Day 9 to Day 11)
Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, corrected QT (QTc-Bazett \[QTcB\], QTC interval-Fredericia\[QTcF\]) intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.
Number of Participants With Hematology Data Outside the Range of PCI for Part B
Time Frame: Day 3 and follow up (Day 17 to 19)
Hematology parameters assessed were basophils (high \>0.1x10\^9 cells/Liter), eosinophils (high \>0.44x 10\^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low \<0.8x10\^9 cells/Liter), MCH (low \<28 picograms and high \>32 picograms), MCHC (low \<32 grams/liter and high \>36 grams/liter), MCV, monocytes (high \>0.208x10\^9 cells/Liter), platelet count, RBC count (low \<4.2x10\^6 cells/microliter and high 5.9x10\^6 cells/microliter) count, total neutrophils and WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.
Number of Participants With Hematology Data Outside the Range of PCI for Part C
Time Frame: Day 1, Day 7 and follow up (Day 23)
Hematology parameters assessed were basophils (high \>0.1x10\^9 cells/Liter), eosinophils (high \>0.44x 10\^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low \<0.8x10\^9 cells/Liter), MCH (low \<28 picograms and high \>32 picograms), MCHC low \<32 grams/liter and high \>36 grams/liter), MCV, monocytes (high \>0.208x10\^9 cells/Liter), platelet count, RBC count (low \<4.2x10\^6 cells/microliter and high 5.9x10\^6 cells/microliter) count, total neutrophils and WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.
Number of Participants With AEs and SAEs Defined by Severity Part B
Time Frame: Up to 19 days
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. AE and SAE were categorized as mild=an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities, moderate=an event that was sufficiently discomforting to interfere with normal everyday activities and severe=an event that prevented normal everyday activities. Data is presented according to the percentage BSA as it impacted safety
Change From Baseline in Vital Sign Parameters SBP and DBP for Part B
Time Frame: Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up (Day 17 to Day 19)
Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.
Change From Baseline in Vital Sign SBP and DBP for Part C
Time Frame: Baseline (Day 1 pre-dose) and Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15 and follow-up (Day 23)
Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1 (pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed.
Number of Participants With Clinical Chemistry Data Outside the Range of Potential Clinical Importance (PCI) for Part A
Time Frame: Day 4 and follow up (Day 5 to Day 7)
Clinical chemistry parameters assessed were alanine amino transferase (ALT), albumin (low \<30 grams/liter), alkaline phosphatase, aspartate aminotransferase (AST), calcium (low \<2 millimoles/liter and high \>2.75 millimoles/liter), chloride, creatinine (high \>159 micromoles/liter), direct bilirubin, gamma glutamyl transferase (GGT low \<8 units/liter and high \>78 units/liter), glucose (low \<3 millimoles/liter and high \>11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low \<3 millimoles/liter and high \>5.5 millimoles/liter), sodium (low \<130 millimoles/liter and high \>150 millimoles/liter), total bilirubin, total protein and urea/blood urea nitrogen (BUN). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.
Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part A
Time Frame: Day 5, Day 7 and follow up (Day 9 to Day 11)
Clinical chemistry parameters assessed were alanine amino transferase (ALT), albumin (low \<30 grams/liter), alkaline phosphatase, AST, calcium (low \<2 millimoles/liter and high \>2.75 millimoles/liter), chloride, creatinine (high \>159 micromoles/liter), direct bilirubin, GGT (low \<8 units/liter and high \>78 units/liter), glucose (low \<3 millimoles/liter and high \>11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low \<3 millimoles/liter and high \>5.5 millimoles/liter), sodium (low \<130 millimoles/liter and high \>150 millimoles/liter), total bilirubin, total protein and urea/BUN). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.
Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part C
Time Frame: Day 1, Day 7 and follow up (Day 23)
Clinical chemistry parameters assessed were ALT, albumin (low \<30 grams/liter), alkaline phosphatase, AST, calcium (low \<2 millimoles/liter and high \>2.75 millimoles/liter), chloride (low \<98 millimoles/liter and high \>106 millimoles/liter), creatinine (high \>159 micromoles/liter), direct bilirubin, GGT (low \<8 units/liter and high \>78 units/liter), glucose (low \<3 millimoles/liter and high \>11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low \<3 millimoles/liter and high \>5.5 millimoles/liter), sodium (low \<130 millimoles/liter and high \>150 millimoles/liter), total bilirubin, total protein (low \<60 grams/liter and high \>78 grams/liter) and urea/BUN (low \<2.9 millimoles/liter and high \>7.1 millimoles/liter). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.
Number of Participants With Hematology Data Outside the Range of PCI for Part A
Time Frame: Day 5, Day 7 and follow up (Day 9 to Day 11)
Hematology parameters assessed were basophils (high \>0.1x10\^9 cells/Liter), eosinophils (high \>0.44x 10\^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low \<0.8x10\^9 cells/Liter), MCH (low \<28 picograms and high \>32 picograms), MCHC (low \<32 grams/liter and high \>36 grams/liter), MCV, monocytes (high \>0.208x10\^9 cells/Liter), platelet count, RBC count (low \<4.2x10\^6 cells/microliter and high 5.9x10\^6 cells/microliter) count, total neutrophils, WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.
Number of Participants With Tolerability Assessment for Part A
Time Frame: Up to Day 4
Tolerability was assessed with the skin irritation scoring system of study, where the score consists of a numeric score according to the dermal response scoring as follows 0=no evidence of irritation, 1=minimal erythema, barely perceptible (pink), 2=moderate erythema (definite redness), 3=strong erythema (intense redness), 4=definite edema, 5=erythema, edema, and papules, 6=vesicular eruption, 7=strong reaction spreading beyond test site, and a letter according to the other effects scoring, Z=no other effect, A=slight glazed appearance, B=marked glazing, C=glazing with peeling and cracking, F=glazing with fissures, G=film of dried serous exudate covering all or part of the patch site, H=small petechial erosions and/or scabs. For each skin assessment, letter grade will be converted to numeric values as below: A=0, Z=0, B=1, C=2, F=3, G=3, H=3. A combined score for each participant was calculated by adding all numeric and letter scores. A maximum score of 3 was allowed.
Number of Participants With Tolerability Assessment for Part B
Time Frame: Up to Day 3
Tolerability was assessed with the skin irritation scoring system of study, where the score consists of a numeric score according to the dermal response scoring as follows 0=no evidence of irritation, 1=minimal erythema, barely perceptible (pink), 2=moderate erythema (definite redness), 3=strong erythema (intense redness), 4=definite edema, 5=erythema, edema, and papules, 6=vesicular eruption, 7=strong reaction spreading beyond test site, and a letter according to the other effects scoring, Z=no other effect, A=slight glazed appearance, B=marked glazing, C=glazing with peeling and cracking, F=glazing with fissures, G=film of dried serous exudate covering all or part of the patch site, H=small petechial erosions and/or scabs. For each skin assessment, letter grade will be converted to numeric values as below: A=0, Z=0, B=1, C=2, F=3, G=3, H=3. A combined score for each participant was calculated by adding all numeric and letter scores. A maximum score of 3 was allowed.
Number of Participants With Tolerability Assessment for Part C
Time Frame: Up to Day 7
Tolerability was assessed with the skin irritation scoring system of study, where the score consists of a numeric score according to the dermal response scoring as follows 0=no evidence of irritation, 1=minimal erythema, barely perceptible (pink), 2=moderate erythema (definite redness), 3=strong erythema (intense redness), 4=definite edema, 5=erythema, edema, and papules, 6=vesicular eruption, 7=strong reaction spreading beyond test site, and a letter according to the other effects scoring, Z=no other effect, A=slight glazed appearance, B=marked glazing, C=glazing with peeling and cracking, F=glazing with fissures, G=film of dried serous exudate covering all or part of the patch site, H=small petechial erosions and/or scabs. For each skin assessment, letter grade will be converted to numeric values as below: A=0, Z=0, B=1, C=2, F=3, G=3, H=3. A combined score for each participant was calculated by adding all numeric and letter scores. A maximum score of 3 was allowed.
Secondary Outcomes
- Plasma GSK2646264 PK Concentrations for Part C(Day 1 (Pre-dose,1 and 4 hours), Day 4 (Pre-dose and 4 hours), Day 7 (Pre-dose and 4 hours), Day 10, Day 15 and follow-up (Day 23))
- t1/2 of GSK2646264 for Part A(Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose at Day 5 (30 and 36 hours), Day 6 (48,54 and 60 hours), Day 7 (72,78 and 84 hours) and Day 8 (96 hours))
- Terminal Half-life (t1/2) of GSK2646264 for Part B(Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3)
- Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of GSK2646264 for Part A(Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2 and Day 3)
- Maximum Plasma Concentration (Cmax) of GSK2646264 for Part A(Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2 and Day 3)
- Time to Cmax (Tmax) of GSK2646264 for Part A(Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2 and Day 3)
- AUC (0-t) of GSK2646264 for Part A(Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose)
- Plasma GSK2646264 Pharmacokinetic (PK) Concentrations for Part A(Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (1,2,4,8,12,24 hours), Day 3 (1,2,4,8,12,24 hours) and Day 4 post-dose at Day 5 (30 and 36 hours), Day 6 (48,54 and 60 hours), Day 7 (72,78 and 84 hours) and Day 8 (96 hours))
- Plasma GSK2646264 PK Concentrations for Part B(Day 1 (Pre-dose,1,4,8,12,24 hours), Day 2 (1,4,8,12,24 hours), Day 3 (1,4,8,12,24 hours), Day 6, Day 9, Day 12, Day 15 and follow-up (Day 17 to 19))
- Terminal Half-life (t1/2) of GSK2646264 for Part A(Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2,3 and 4)
- Cmax of GSK2646264 for Part B(Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3 (Day 4))
- Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of GSK2646264 for Part B(Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3)
- Tmax of GSK2646264 for Part B(Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3)
- Cmax of GSK2646264 for Part C(Pre dose and 4 hours post-dose on Days 1, 4 and 7)
- Tmax of GSK2646264 for Part C(Pre dose and 4 hours post-dose on Days 1, 4 and 7)
- Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK2646264 for Part A(Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2,3 and 4)
- Tmax of GSK2646264 for Part A(Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose)
- AUC [0-t] of GSK2646264 for Part B(Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3)
- Cmax of GSK2646264 for Part A(Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose)
- AUC (0-24) of GSK2646264 for Part B(Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3 (Day 4))
- t1/2 of GSK2646264 for Part C(Pre dose and 4 hours post-dose on Days 1, 4 and 7)